Cataract extraction is among the most commonly performed operations in the world. The natural lens is located within a capsular bag, also called lens capsule or capsular sac, which is located in the posterior chamber of the anterior segments of the eye. In order to gain access to the natural lens, an incision is made either in either the clear cornea, at the limbus, or in the sclera of the eye whereby it becomes possible to introduce surgical instruments into the anterior segments of the eye. In the case of cataract extraction, an opening is made in the capsular bag, currently mostly by a capsular a capsulorhexis technique, whereby a portion of the anterior membrane of the capsular bag is torn out to allow insertion of surgical instruments into the capsular bag for the purpose of extraction of the natural lens. The natural lens can be removed through by application of many known techniques, including what is known as phacoemulsification.
Phacoemulsification is a method that entails the application of ultrasonic energy or other forms of energy to the natural lens thus breaking said lens into fragments, which can then be aspirated from the capsular bag. The capsular bag remains substantially intact throughout the process of cataract extraction, with the exception of the portion removed to prepare access for the surgical instruments used in the extraction of the natural lens. After the removal of the natural lens (aphakia), an artificial intraocular lens (IOL) implant is implanted within the capsular bag in order to mimic the transparency and the refractive function of a natural lens. Alternatively a lens material is injected to fill the capsular bag and thus an artificial lens is created in situ. Such lenses (ACL) can in addition restore the accommodative function of the natural lens before the onset of presbyopia (loss of ability to accommodate).
In modern cataract extraction surgery, especially with phacoemulsification, one feature of the surgical technique is to separate the natural lens from the capsular bag, one such a technique is hydrodissection. In this technique a fluid wave is injected under the anterior capsule in such a way that it separates the lens from the capsular bag. One of the most common used fluids for the purpose of hydrodissection is a balanced salt solution, which is both ionically and osmotically balanced with regard to the aqueous humor and internal tissue of the eye. In addition to sodium chloride, said solution contains also potassium chloride, calcium chloride, magnesium chloride, sodium acetate and sodium citrate. The balanced salt solutions are considered to be physiologically compatible with the ocular tissue since they contain the essential ions for normal cell metabolism.
Lens removal with IOL or ACL implantation replacement provides significant benefits to most cataract patients. Currently lens removal with artificial lens implantation is increasingly carried out in a non-catarcatous eye, so-called refractive lens exchange, often with the purpose to relieve presbyopia. However, it is estimated that up to fifty percent of all patients, who have implants placed within the capsular bag, will develop capsular opacification (CO), also known as secondary cataract or aftercataract, within five years after surgery. CO is an opacification located on the inner surface of capsular bag, whether located posteriorly (PCO) or anteriorly (ACO). CO is caused by deposition or ingrowth of cells, cell derivatives and/or fibers into the visual axis and might also be caused by extracellular matrix produced by the lens epithelial cells, thereby impairing the optical axis of the eye and thus clouding of the vision. Thus, the cell deposits on the capsule and/or on the implant originate from the proliferation and migration of residual lens epithelial cells on the interior surface of the capsular bag and the production of extracellular matrix by these cells. During cataract surgery, the surgeon removes the lens and replaces it with a new artificial lens.
Ophthalmic surgeons, aware of the problems associated with residual lens epithelial cells, typically take considerable care in trying to remove as many as possible of the lens epithelial cells prior to implantation of an artificial lens (IOL or ACL). However, despite these efforts, a significant number of lens epithelial cells are usually left on the interior surface of the capsular bag since these cells are difficult to view and often difficult to reach and virtually impossible to completely remove.
The most common treatment for postoperative PCO uses laser energy, which is applied to the posterior membrane of the capsular bag for the purpose of creating an opening in the posterior capsule (known as Nd-YAG capsulotomy). However, the laser energy applied to the posterior membrane of the capsular bag is ordinarily directed through the implant and might damage the optic of said implant. Accordingly, it is preferred to prevent the occurrence of CO rather than treating CO at a later date through the application of laser energy. This is especially desirable when the implant is accommodating response to ciliary muscle contraction, in which case a capsulotomy may compromise the accommodative ability of the lens
Various procedures for the prevention of CO have been suggested in recent years. These include administration of antimetabolites (such as 5-flurouracil, adunomycin and doxorubicin), irrigation with hypotonic solutions, irrigation with chelating agents, administration of cytotoxic agents (such as saporin) conjugated to target seeking molecules like polylysine, antibodies and fibroblast growth factors. However, few if any of these procedures have proven to be particularly successful in the prevention of CO due to the fact that it is extremely difficult to destroy residual lens epithelial cells without simultaneously destroying other cells within the eye, e.g. there exists a number of chemical agents that could kill the lens epithelial cells, however, said agents may also adversely affect other cells within the eye, in particular corneal endothelial cells. Thus, selective destruction of residual lens epithelial cells by exploitation of the cells increased proliferate activity has thus been the primary approach for the prevention of CO. Many of these suggested therapies would also be costly and difficult to reliably apply on consistent basis.
Antimetabolites such as 5-fluorouracil (5FU) and daunomycin have been injected into the capsular bags of eyes in attempts to prevent CO. However, for antimetabolite therapy to be effective, the agents must be present when the residual lens epithelial cell proliferation resumes at an indeterminate time following surgery. Sustained drug delivery systems have also been investigated as means for preventing CO. However, the effective time frame within when to apply these agents may likewise be difficult to determine. Thus, timing is difficult in the prevention of CO since it, as mentioned above, is believed to result primarily from the propagation of residual lens epithelial cells of the germinal layer and it is difficult to accurately predict when said cells might start to proliferate and migrate across the capsular bag into the optical zone.
In order to reduce risks of contacting other eye tissues with hazardous agents WO 02/15828 (Bausch and Lomb) suggests to seal the capsular bag with the lens removing instrument by means of which PCO treating agents can be introduced methods for removing epithelial cells by injecting a composition comprising an agent after the natural lens has been removed from the capsular bag.
Another approach to obtain control of the PCO treatment step would be to use a viscoelastic solution or a gel which can be introduced and removed with adequate control compared to plain solutions. The viscoelastic solutions or gels can also serve to maintain the concentration of the agent as disclosed in U.S. Pat. No. 5,110,090 (Krumeich) or to protect the tissues of the anterior chamber from agents injected into the capsular bag as disclosed in U.S. Pat. No. 4,909,784 (Dubroff). U.S. Pat. No. 5,061,696 (York) suggests to fill the lens free capsular bag with air and then inject a hypotonic viscoelastic that is capable to rupture unwanted epithelial cells with osmotic swelling. WO 96/34629 suggests a sustained release preparation of cytotoxic agent complexed to hyaluronic acid that is implanted in a suitable position following the surgical process. None of these techniques provide a satisfying solution to completely inhibit postsurgical growth of epithelial cells. For capsular opacification treatment with viscoelastic, the present inventors have experienced uneven results such that certain parts of the inner capsular bag appear inadequately treated resulting in epithelial cell growth in strains. Apparently, there is still a need of a reliable and safe way of preventing capsular opacification in conjunction with a surgical process for lens replacement.